Imidazolido thiophanes and methods of preparing same



Patented June 7, 1949 IMIDAZOLIDO THIOPHANES AND METHODS OF PREPARINGSAME Bernard R. Baker, Nanuet, and Merle V. Querry,

Pearl River, N. Y., assignors, by mesne assignments, to AmericanCyanamid Company, New York, N. Y., a corporation of Maine No Drawing.Application August 14, 1945, Serial No. 610,872

11 Claims. 1

The present invention relates to new organic compounds. Moreparticularly it relates to substituted imidazolido thiophanes andmethods of preparing the same.

The new compounds of the present invention can be illustrated by thefollowing general formula:

in which X is a hydrogen, aromatic or an all phatic radical and R and Rare hydrogen or N- substituted carbamidoalkyl radicals.

We can prepare the new compounds of the present invention by mixing asubstituted ureylenethiophane carboxhydrazide with nitrous acid in asolvent.

The compounds of the present invention are White solids. They aresoluble in methanol, ethanol, butanol, and other hydroxylated s01-vents, acetone, acetic acid, dioxane, pyridine, etc. They haverelatively high melting points.

The ureylenethiophane carboxhydrazides used as intermediates in thepresent invention are described and claimed in our copending applicationSerial No. 610,682, filed August 13, 1945, now U. S. Patent No.2,451,429.

' Among the intermediates we can use, the following may be mentionedspecifically: Z-(deltacarbanilidobutyl) 4 uranilinothiophane3-ciscarboxhydrazide, 2-'( delta methylcarbamidobutyl)-4-uranilinothiophane 3 cis-carboxhydrazide, 2-delta-ethylcarbamidobutyl) -4-uranilinothiophane-3-cls-carboxhydrazide,2-( delta carbanilidobutyl)-4-methyluramidothiophane-3-ciscarboxhydrazlde, Z-(delta nmethylcarbamidobutyl) -4-methyluramidothiophane-3-cis -carboxhydrazide,2- (delta-ethylcarbamidobutyl) -4-methyluramidothiophane 3cis-carboxhydrazide, 3- uranilinothiophane' 4 cis carbo-xhydrazide, 3-methyluramidothl'ophane 4-cis carboxhydrazide, 2 (deltacarbanilidobutyl) 3 uranilinothiophane-4-cis-carboxhydrazide, 2-delta-carbanilidobutyl) -3 methyluramidothiophane-4-ciscarboxhydrazideand thelike.

We have found, unexpectedly, that when compounds such. as those listedabove are heated With nitrous acid in the presence of a solvent, notonly does the carboxhydrazide radical rearrange to an amine derivative,but an imidazolido thiophane ring is formed as well. Those compoundswhich have in the 2-position a carboxybutyl orsubstituted carboxybutylradical are particularly valuable in the synthesis of biotin. They canbe heated with barium hydroxide to form 2-(delta--carboxybutyl)-3,4-c-is diaminothiophane, which when treated withphosgene gives d1 biotin, as shown in Example 1.

In carrying out the reaction we can use nitrous acid itself although weprefer to prepare the nitrous acid in the reaction mixture during thecourse of the reaction by adding to the mixture alkyl mtrites, such asmethyl nitrite, ethyl nitrite, amyl nitrite, isoamyl nitrite, etc.,salts of nitrous acid, such as, sodium nitrite, potassium nitrite,ammonium nitrite, etc., and an acid.

In preparing the compounds of our invention we prefer to carry out. thereaction under anhydrous conditions as the yields are higher and thereaction proceeds more smoothly. The reaction is carried out by mixingthe desired intermediate with an anhydrous solvent such as anhydrousmethanol, ethanol, propanol, butanol, etc. and a small amount of anacid. We can use acids such.

as hydrochloric, sulfuric, nitric, acetic, phosphoric, etc., but weprefer to use a solution of hydrogen chloride in an anhydrous solvent asthis aids in maintaining anhydrous conditions in the reaction mixture. Anitrite is added, preferably an alkyl nitrite. The. reaction can becarried out at tempertures ranging from 0 C. to 125 C. and is usuallycompleted in from about onehalf hour to about twenty-four hours. Weprefer, however, to carry out the reaction at a temperature of fromabout C. to about C. at Which temperature the reaction is generallycomplete in from about one-half hour to about three hours.

- The product can be recovered from the reaction mixture by evaporatingthe solvent and crystallizing the residue from methanol,benzene-petroleum ethermixtures, etc:

Our invention will now be illustrated in greater detail bymeans of thefollowing specific examples in which representative ureylenethiophane 3carboxhydrazides are converted to the corresponding imidazolidothiophanes. It will be understood, of course, that these examples aregiven for purposes of illustration and are not to be considered aslimiting our invention to the particular details described therein.

Example 1 moved in vacuo, the residue cooled and triturated withmethanol. A yield of 1.83 g. (51%) of 2- (delta-carbanilidobutyl)-5-keto-6-carbanilidoimidazolido [4,5,c,cis] thiophane was obtainedwhich on recrystallization from methanol gave white crystals melting at214-216 C.

A mixture of 2.0 g. of Z-(delta-carbanilidobutyl)-5-keto-G-carbanilidoimidazolido [4,5,c,cis] thiophane, cc. of 50%methanol and 8 g. of barium hydroxide octahydrate was heated and shakenin a bomb at 160 C. for forty hours. The bomb contents were rinsed outwith water and the excess baryta removed with Dry Ice. The filtrate,washed three times with chloroform to remove aniline, was made just blueto Congo red by th addition of 1 N sulfuric acid cc.).

After removal of the barium sulfate the solution was evaporated todryness in vacuo and triturated with methanol. The almost colorlesscrystals were collected on a filter and washed with methanol. A yield of.76 g. (53%) of 2 (delta carboxybutyl) 3,4 ci-s diaminothiophane sulfatewas obtained which melted at 257258 C. with decomposition.

A clarified solution of 650 mg. of 2-(deltacarboxybutyl)3,4-cis-diaminothiophane sulfate in 26 cc. of 10% potassium carbonatewas treated with phosgene with shaking and ice cooling until acidic. Thewhite crystals which separated were collected on a filter and washedwith ice water. A yield of 450 mg. (90%) of2-(delta-carboxybutyl)-5-ketoimidazolido [4,5,c,cisl thiophane(dl-biotin) was obtained. When recrystallized from 50% aqueous methanolthe product was in the form of long white needles which had a meltingpoint of 230-232 C. An assay with Lactobacillus arabinosis showed thatthis product had 52% of the activity of natural d-biotin.

Example 2 To a stirred solution of 1.9 g. ofci-s-4-uranilinothiophane-S-carbcxhydrazide in '70 cc. of 1 Nhydrochloric acid and 50 cc, of chloroform was added, with ice cooling,a solution of 0.56 g. of sodium nitrite in 10 cc. of water. Theseparated and dried chloroform layer was refluxed for four hours, thenevaporated. The residue was crystallized from benzene-heptane and gave ayield of 1.17 g. (66%) of 4-carbanilido-5-ketoimidazolido [4,5,c,cis]thiophane. The product recrystallized from benzene-petroleum ether had amelting point of 164-l67 C.

A mixture of 0.67 g. of 4-carbanilido-5-ketoimidazolido [4,5,c,cis]thiophane and 5 cc. of 48% hydrobromic acid was refluxed for sixteenhours.

4 On cooling the solution deposited 0.30 g. of cis- 3,4-diaminothiophanedihydrobromide. The product recrystallized from 48% hydrobromic acidgave white crystals melting at 309-310 C. with decomposition,

A solution of 0.26 g. of cis-3,4-diaminothiophane dihydrobromide in 50cc. of saturated sodium bicarbonate was treated with phosgene at 0. C.until acidic, then evaporated to dryness in vacuo. The residue wasextracted with hot butanol and the extract evaporated. Sublimation at150 C. (1 mm.) gave 60 mg. of 5-ketoimidazolido [4,5,c,cisl thiophane aswhite crystals having a melting point of 231 C.

Example 3 To a hot suspension of 150 mg. of Z-(deIta-carbanilidobutyl) 4uranilinothiophane 3 ciscarbohydrazide in cc. of dry methanol was addeda solution of 0.42 g. of hydrogen chloride in 5 cc. of methanol. To theclear solution was added 1.04 cc. of butyl nitrite with swirling. Thesolution was then refluxed for about an hour, gas evolution beingcomplete in five minutes. Solvent was removed in vacuo and the residuecooled and triturated with methanol. 63.0 mg. of2-(delta-carbanilidobutyl) -5-keto-6- carbanilidoimidazolido [4,5,c,cislthiophane was obtained.

Example 4 To a hot suspension of mg. of 2-(delta-carbanilidobutyl) 4uranilinothiophane 3 cis carboxhydrazide in 125 cc. of dry butanol wasadded a solution of 0.42 g. of hydrogen chloride in 5 cc. of butanol. Tothe clear solution was added 1.04 cc. of butyl nitrite with swirling.The reaction mixture was maintained at 55 C. for 2 hours. The reactionwas completed by heating at 100 C. for one hour. The solvent was removedin vacuo and the residue cooled and triturated with methanol. A yield of59.0 mg. of z-(delta-carbanilidobutyl) -5-keto-(i-carbanilidoimidazolido[4,5,c,cisl thiophane was obtained.

We claim:

1. Chemical compounds having the general formula:

in which X is a member of the group consisting of hydrogen, alkyl andaryl radicals, and R and R are members of the group consisting ofhydrogen, N-alkyl carbamidoalkyl radicals and N-aryl carbamidoalkylradicals.

2. Chemical compounds having the general formula:

in which R and R are members of the group consisting of hydrogen,N-alkyl carbamidoalkyl radicals and N-aryl carbamidoalkyl radicals.

A yield 01'' 3. Chemical compounds having the general formula:

H o E Haia H ii "12:, H H

in which X is a member of the group consisting of hydrogen, aryl andalkyl radicals and R and R are members of the group consisting ofhydrogen, N-alkyl carbamidoalkyl radicals and N-aryl carbamidoalkylradicals which comprises mixing a compound having the formula:

in which X, R and R' are as defined above, with a nitrite in thepresence of a mineral acid and a lower aliphatic alcohol.

8. A method of preparing compounds having the general formula:

H o a Mary M ii iii 6 in which X is a member of the group consisting ofhydrogen, alkyl and aryl radicals and R and R are members of the groupconsisting of hydrogen, N-alkyl carbamidoalkyl radicals and N-arylcarbamidoalkyl radicals, which comprises heating a compound having theformula:

HNC ONH-X O ONHNH:

in which X, R and R are as defined above, with a. nitrite in thepresence of a mineral acid and a lower aliphatic alcohol at atemperature of from about C. to C. for from about one-half hour to aboutthree hours.

9. A method of preparing 2- (delta-carbanilidobutyl)5-keto6-carbanilidoimidazolido [4,5,c,cis] triophane which comprisesmixing 2-(delta-carbanilidobutyl) 4 uranilinothiophane 3 ciscarboxhydrazide with an alkyl nitrite in the presence of hydrogenchloride and a low molecular monohydric alkyl alcohol.

10. A method of preparing z-(delta-carbanilidobutyl) 5 keto 6 Nmethylcarbamidoimidazolido [4,5,c,cis] thiophane which comprises mixing2 (delta carbanilidobutyl) 4methyluramidothiophane-3cis-carboxyhydrazide with an alkyl nitrite inthe presence of hydrogen chloride and a low molecular monohydric alkyla1- cohol.

11. A method of preparing 2-(delta-carbanilidobutyl) 5 keto 6 Nethylcarbamidoimidazolido [4,5,c,cisl thiophane which comprises mixing2- (delta-carbanilidobutyl)4-ethy1uramidothiophane-8-cis-carboxyhydrazide with an alkyl nitrite inthe presence of hydrogen chloride and a low molecular monohydric alkylalcohol.

BERNARD R. BAKER. MERLE V. QUERRY.

No references cited.

